Sulfonamido-s-substituted isothioureas



Patented May 18, 1948 SULFON-AMIDO-S-SUBSTITUTED ISOTHIDUREAS Edward H. Cox, swarthmore, and JamesuM.

Sprague, DrexelHill, Pa., assignorstosharpdr Dohmre, Incorporated, Philadelphia, Pa, acorporationof Maryland No Drawing; ApplicationJanuary l3, 1942,

Serial N0. 426,564

4 Claims. ,1

This invention relatesto arylsulIonyl-s-substituted-isothiou-reas and their preparation, and more particularly -torthe class or compounds; represented by theiollowing general formulae:

in which M; may be. para or ortho to the suifonyl group and may :be hydro en, a ha radical as chlorine orbromi-ne, or :2. nitro, amino,

or ;alkyl-, acy1- or acylalkyd-amino group (and the alkyl, 'acyl or acylalk-yl group. thereof may be saturated or unsaturated such as methyl, ethyl, buty-l, allyl, hexyl and the like,;-1s,traig-ht or branched chain, suchas isoamyl, or substituted as 2-ehloro-propylor non-substituted Aris an aryl radical such .asthe phenyl or substituted phenyl, or naphthyl or substituted n'aphthyl and the like; and R, R1 and'Rz may be separately hydrogen, an ,alkylgroup of the type as .noted above for the alkyl radical-in. the substituted amino group .or .M and having even up to eighteen or more carbon atoms, an aryl. radical, onub- "-1 -inabovedescribed for R1 and R2, with an alkylatsti-tuted as phenyl or naphthyl and the'like or substituted as chloro-phenylj, tolylj, .xylyl andthe like, or aralkyl as benzyl and the. like.

The compounds of theinvention areusefulas chemotherapeutic agents and-es intermediates in the preparation of other compounds.

The compounds of the invention are not restricted to any single method of preparation although partof the invention is the preparation Of-thBSG compounds by condensing any selected -:'J

S-substituted isothiourea compound havin a replaceable hydrogen attachedto nitrogen (using the S-substituted-isothiourea either as thefree base or as a salt thereof) witha suitable arylsula-nitro or diazoigroup which is convertible to an aminop'group by'reduction, which arylsul'fonyl- S-substituted-isothiourea is then hydrolyzed or reduced, as the case may require, to the desired aminoarylsulfonyl-s substituted-isothiourea.

In. the reactionbetween the S-substitutedisothiourea icompound and the arylsulfonyl halvide, a hydrogenhalideis liberated. Therefore,

to improve the yle1d,,it' is desirable toprovide a basic substance, such 'as sodium hydroxide, sodium bicarbonate, potassium carbonate or pyridine or other alkaline acting substance, to unite with the hydrogen halide liberated in the reaction. The reaction with the described agents may be ca-rriedout ina suitable medium such as water, acetone and the like.

The desired S-alkyl-isothiourea may be prepared by reacting therequired thiourea, having the general-formula v r in which any twolof the Rsare hydrogen and the other two R's are separately hydrogen or an fonyl halide having no unsubstituted amino group attached :to ,thearyl nucleus. To obtain the arylsulionyl-S substituted -isothiourea having an unsubstituted amino group linked: to the aryl nucleus, first there is prepared, for example,

by the method J'ustgiven, the corresponding aryli alkyl, aralkyl or aryl group of the type as hereingagent, for example, an alkyl or aralkyl halide, as methyl iodide; or bromide or ethyl chloride or bromide or benzyl chloride, or an alkyl sulfate asdiethyl sulfate, or an alkyl sulfonate, and the like, whereby one of the replaceable hydro'gens represented-by one of the Rs is replaced by the selected alkyl or aralkyl radical to yield the desired S-alkyleisoth-ioureasalt from which the-de- -S .a1k ,y1.-i50thi()u111e9, may be obtained in kIlOWl'l. manner.

Th intention may be illustrated by, but not restrictedto, the following examples:

Example1- -Benzenesulfonyl S ethylisothiowear-37:0 :g of 'S-ethylisothiourea hydrobromide was dissolved in water and 35 .3 g. of benzenersulfonyl ch-loride added. The mixture was vigorous y a itated-anda solution of 10% sodium lmdroxide added :at such- ;a rate that the reaction mixture was kept slightly alkaline. When the Vreactionwascompleite, as shown by a permanent- 1y alkaline reaction, the solid desired end-prodnot was removed by. filtration and recrystallized from dilute alcohol or from a. mixture of benzene petroleum ether, its M. Pt. was ,l Q9- -1 10'C.

tained respectively the following arylsulfony-l.

methyl-iso-thioureas having the corresponding melting points (in C.) shown:

Benzenesulfonyl-S-methy1lsothlourea p Toluenesulfonyl S methylisothiourea 118-119 3,4 dimethylpheny-lsulfonyl-S-methylisothiourea 136-137 2,4 dimethylphenylsulfonyl-S-methylisothiourea 137-138" 2,5 dimethylphenylsulfonyl-S-methylisothiourea 144- 145 Example 2p-Acetylaminobenzenesulfonyl-S- methyZ-isothiourea.-In a three liter flask provided with a motor stirrer was placed 400 g. of anhydrous potassium carbonate and one liter of acetone to which hadbeen added 300 cc. water. The suspension was stirred and cooled in an ice bath. To this was added a mixture of 153 g. (1.1 moles) of S-methyl-isothiourea sulfate and 234-. g. (1.0 mole) of p-acetylamlnobenzenesullfonyl chloride over a period of half an hour. After the addition, the ice bathwas removed and'the reaction mixture stirred for four hours. The reaction contents were then poured while stirring into four liters of water, filtered, and washed with water. When dried, the crude product weighed 228 g. (yield 80%). After crystallization from dilute alcohol, smallfcolorless needles of p-acetylaminobenzenesulfonyl -S methyl-isothiourea were deposited which melted at 230-232 C.

Example 3p-Aminobenzenesulfonyl-S-methyl-isothioarea.-Two hundred grams of p-acetamlnobenzenesulfonyl S methyl-ism thiourea (product of Example 2) was suspended in 1200 cc. of 7% hydrochloric acid solution. The flask was lowered into a boiling water bath and mechanically stirred. until solution took place (-45 mins.) The solution was then treated with half volume. of water (to prevent the crystallization of the hydrochloride salt). It was then cooled in an ice bath and made alkaline with ammonia (with stirring). The crude product was filtered, washed, and dried (128 g., yield), and after being twice crystallized from dilute acetic acid, it melted at 183-185 C. (colorless white needles).

7 Example 4p-Acetylaminobenzenesulfonyl-S- ethylisothioarea.A solution of 55.5 g. of S-ethylisothiourea hydrobromide in cc. of water and a solution of 70.0 g. of p-acetylaminobenzenesulionyl chloride in 350 cc. of acetone were mixed and a solution of 15.0 g. of sodium hydroxide in cc. of water added slowly from a dropping funnel. The reaction mixture was vigorously stirred and the internal temperature maintained at 10-15 C. during the addition of the alkali. When the reaction mixture remained permanently alkaline, the product was removed by filtration and recrystallized from dilute alcohol, M. Pt. 181.5-182" C.

Example 5p-AminobenzenesuZfonyl-S-ethylzsothioarea'.The acetylaminobenzenesulfonyl-S- ethylisothiourea was suspended in 1:7 hydrochloric acid (12 cc. per gram) and ethyl alcohol '4 added (1 cc. per gram). This mixture was heated, with stirring, on a water bath until all the solid had dissolved. The solution was cooled and neutralized with sodium bicarbonate. The precipitated product was separated and recrystallized from alcohol, M. Pt. -161.5 C.

Example 6-p-Acetylaminobenzenesulfonyl-S- n-hexylisothiourea.This was prepared from p-acetylaminobenzenesulfonyl chloride and S-nhexylisothiourea in a manner similar to that described in Example 4, M. Pt. 125.5l26 C.

Example 7p-AminobenzenesuZfonyl-S-n-he:cylzsothiourea.-The product from Example 6 was hydrolyzed with dilute hydrochloric acid as described in Example 5 for the ethyl derivative and recrystallized ,from dilute alcohol, M. Pt. 129- 130.5 C. 7

.By replacing the benzenesulfonyl chloride of Example .Lby an equimolecular quantity of any other desired arylsulfonyl halide, such as por o-nitrobenzen'esulfonyl chloride, or por o-acetylethylaminobenzenesulfonyl chloride, there is obtained respectively the corresponding por o-nitrobenzenesulfonyl-S-ethyl-isothiourea, the por o-ethylaminobenzenesulfonyl-S-ethyl-isothiourea, or .the por o-acetylethylaminobenzenesulfonyl-S-ethyl-isothiourea.

Also, by replacing the p-acetylaminobenzenesulfonyl chloride of Example 2 by an equimolecular quantity of any other por o-acylaminobenzenesulfonyl halide, there is obtained the corresponding por 0-acylaminobenzenesulfonyl-S- methylisothiourea.

Further, by replacing the S-alkyl-isothiourea of any of the Examples 1, 2, l and 6 by any other S-alkyl-isothiourea, or by any S-aralkyl-isothiourea, as S-benzyl-isothiourea, or any S-arylisothiourea as S-phenyl-isothiourea, there are obtained respectively the corresponding arylsulfonyl-S-alkyl-isothioureas, or arylsulfonyl-S- aralkyl-isothioureas, and arylsulfonyl-S-arylisothioureas.

Thus, while variations in the starting materials employed for preparing the products of the invention, as hereinabove indicated, give the various types and classes of products and the various specific products particularly mentioned hereinabove, the invention also includes products such as por o-aminobenzenesulfonyl-S-ethyl-N- methyl-isothiourea or other corresponding compounds in which the N-methyl group in the product last described is replaced by any other alkyl, or by an aralkyl or aryl group, or the corresponding compounds in which the amino group ortho or para to the sulfonyl radical is replaced by a substituted-amino group or 2. nitro group or hydrogen.

Of those compounds of the invention in which a nitro or an amino (whether substituted or unsubstituted) group is linked to the aryl radical represented by Ar in the general formula, those in which such nitro or amino group is para in position to the sulfonyl group are the more chemotherapeutically active.

We claim:

1. The compound sulfanilyl ethyl isothiourea.

2. A compound represented by the following formula:

mNOSmN-( I-SP. i sin in which Ris an alkyl radical.

3. The compound sulfanilyl S-methyl isothir a 4. The compound sulfanilyl S-n-hexyl isothi- FOREIGN PATENTS ourea Number Country Date v 542,319 Great Britain Jan. 5, 1942 JAMES M. SPRAGUE.

5 OTHER REFERENCES REFERENCES CITED Ganapathi, Indian Academy of Science, Proc., The following references are of record in the vol. 12A, Sep 4 p s 274 t EDWARD H. COX.

file of this patent: Basterfield et aL, Jour. Am. Chem. 800., vol. 49,

. pages 3177-3180 (1927). UNITED STATES PATENTS Basterfield et aL, Can. J. Research, pages 1,261-

1,272 929). Number Name Date Chambers et aL, Ind. Eng. Chem, vol. 16, pages 2,147,346 Johnson Feb. 14, 1939 12724273 1924 

